Alpha-five carbon cyclic hydrocarbon mandelic acid esters of beta-pyrrolidino-ethanol



ALPHA-FIVE CARBON CYCLIC HY DROCARBON MANDELIC ACID ESTERS OF BETA-PYRROLI- DIN O-ETHANOL Robert B. Motfett and John L. White, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, MiclL, a corporation of Michigan No Drawing. Filed Mar. 22, 1954, Ser. No. 417,916 6 Claims. (Cl. 260-3263) This invention relates to novel aminoesters, more particularly to pyrrolidylalkyl esters of disubstituted hydroxyacetic acids. These compounds are physiologically active, especially as antispasmodic and antisecretory agents.

It is an object of the present invention to provide novel pyrrolidylalkyl esters of disubstituted hydroxyacetic acids. Other objects will be apparent to those skilled in the art to which this invention pertains.

The novel pyrrolidylalkyl esters of disubstituted hydroxyacetic acids of the present invention are represented by the following structural formula:

wherein R is a hydrocarbon radical containing from one to twelve carbon atoms, inclusive; R contains less than twelve carbon atoms and is lower-alkyl or a five or six membered cycloalkyl group; R and R together contain a total of more than six carbon atoms; R is a loweralkylene divalent radical having two carbon atoms between its valences; and Am is N-pyrrolidyl or a methyl substituted N-pyrrolidyl radical, acid addition salts thereof, and quaternary ammonium salts thereof.

Examples of hydrocarbon radicals represented by R above are methyl, ethyl, propyl, isopropyl, amyl, isoamyl, hexyl, heptyl, octyl, cyclopentyl, l-methylcyclopentyl, cyclohexyl, 2,4,6-trimethylcyclohexyl, and hendecyl.

Examples of hydrocarbon radicals represented by R above include the R groups named above and n-decyl, n-dodecyl, phenyl, benzyl, 2,4,6-trimethylphenyl, (l-meth ylbenzyl, tolyl, p-biphenylyl, p-cyclohexylphenyl, 2-phenylcyclopentyl, o-cyclohexylphenyl, and naphthyl.

The divalent radical R may be further described by the formula R R R R C 1 In this formula the Rs are hydrogen and/or lower-alkyl groups. Examples of R are the radicals ethylene (CH CH propylene, l-ethyiethylene, 2-ethylethylene, 1,2-dimethylethylene, 1,1-dirnethylethylene, 2,2- dimethylethylene, 1,2,2-trimethylethylene, 1-(n)-hexylethylene, 2-(n)-propylethylene, etc.

Examples of Am include pyrrolidyl, 2-methylpyrrolidyl, 3-methylpyrrolidyl, 2,5-dimethylpyrrolidyl, 2,3-dimethylpyr-rolidyl, 2,2-dimethylpyrrolidyl, 2,2,3-trimethylpyrrolidyl, etc. a

The acid addition salts of the above-described compounds include the hydrochloride, sulfate, acid sulfate, succinate, nitrate, acetate, tar trate, citrate, phosphate, etc. The quaternary ammonium salts include the methobromide, rnethochloride, methiodide, ethiodide, ethochloride,

benzyl chloride, dodecyl chloride, bis-hexamethylene dichloride, etc.

The novel compounds of the present invention can be or bromide. This is conveniently achieved by heating a solution of the acid in acetone or other inert solvent with "ice 2 an acidaddition salt of the pyrrolidylalkyl halide, in the presence of potassium or sodium carbonate or other base capable of reaction with the acid addition salt of the pyrrolidylalkyl halide to produce the free pyrrolidylalkyl halide. The pyrrolidylalkyl chloride hydrochlorides or bromide hydrobrornides are prepared by the reaction of thionyl chloride or bromide, respectively, for example, in the manner described in the preparations hereinafter, with the selected pyrrolidyl alkanol. Examples of the pyrrolidyl alkanols which may be used may be found in the article by Moiiett, J. Org. Chem., 14, 862 (1949) and by Moffett and White, ibid, 17, 407 (1952). The disubstituted hydroxyacetic acids may be prepared in a number of ways, for example, by the reaction of a hydrocarbon magnesium halide with benzoylformic acid or other hydrocarbon-u-ketoacid; by the hydrolysis of the cyanohydrin of a ketone with concentrated sulfuric acid; by the benzilic acid type of rearrangement of an u-diketone; or by the hydrogenation of an unsaturated a-hydroxy acid. For examples of these reactions see: Mc-

, Kenzie and Ritchie, Ber., 70B, 33 (1937); Hofirnann ,acid, a-n-heptylmandelic acid, a-(S-methyIheXyDmandeIic acid, ot-cyclopentyl-a-cyclohexyl-ot-hydroxyacetic acid, a,a-dicyclohexyl-a-hydroxyacetic acid, oz-CYClOperl'tYl-a-l'lpropyl-a-hydroxyacetic acid, a-n-propyl-u-isoamyl-m-hydroxyacetic acid and other acids of the formula wherein R and R have the values given hereinbefore.

Compounds produced by the esterification of a pyrrolidylalkyl chloride or bromide with an a,u-disubstituted- 2,2-dimethylpyrrolidylethyl n-propylmandelate,

Z-methylpyrrolidylethyl n-oetylmandelate,

pyrrolidyl-Z-propyl cyclohexylmandelate,

2,S-dimethylpyrrolidylethyl wcyclopentyl-otacyclohexyl-ahydroxyacetate,

2,5 dimethylpyrrolidylethyl a cyclopentyl-a-n-propyl-ahydroxyacetate,

2,2-dimethylpyrrolidyl-2-propyl a-cyclohexyl-a-n-octyl-ahydroxyacetate,

Z-methylpyrrolidylethyl a-n-propyl-oc-isobutyl-u-hydroxy acetate,

2,5 dimethylpyrrolidylethyl a-n-octyl-a-( l-naphthyD-ahydroxyacetate, and

Z-methylpyrrolidylethyl u-biphenylyl a n propyl-a-hydroxya cetate.

Ordinarily, the boiling point of the reaction mixture, e.g., from about 35 to 100 degrees centigrade, is a satisfactory reaction temperature. The reaction mixture is usually refluxed for several hours to ensure complete re- 1 action. It is usually preferred to employ the acid and the ayketone, ethanol; propanol or diethyl ketone.

pyrroli-dylalkyl ha-lidein equimolar proportions in the reaction.

Although-acetone is a convenient solvent, a higher boil: ing solvent is sometimes preferred, e.g., methyl ethyl used to react with the acid addition salt of the pyrrolidylalkyl halide is usually employed in excess of the amount theoretically required, I

The reaction product can ether. Washing the ether solution with dilute alkali re- The base be isolated by dammit; the :"reaction solvent and dissolving, the organic residue in 3 moves any acidic material and any quaternary ammonium salts. The ether solution can then be dried and the product isolated by distillation to leave the free base as the distillation residue or by preparation of the acid addition' salt or quaternary ammonium salt according to methods known in the art. Ordinarily, the free bases are not stable to distillation and must be purified by other techniques, e.g., as their acid addition salts.

The following examples are illustrative of the products and process of the present invention, but are not to be construed as limiting.

PREPARATION l Isoamylmandelic acid (a-phenyl-a-isoamyl-u-hydroxyacetic acid) To a solution of 97.6 grams (0.65 mole) of benzoylformic acid in 500 milliliters of dry tctrahydrofuran was added the solution of isoamyl magnesium bromide prepared'by the reaction of 211.4 grams (1.4 moles) of isoamyl bromide with about fifty grams (twomoles) of magnesium filings in 500 milliliters of tetrahydrofuran. The resulting mixture was stirred at room temperature for sixteen hours. The thus-produced Grignard complex was carefully decomposed with ice water. Most of the tetrahydrofuran was distilled from the mixture and the aqueous distillation residue was carefully acidified to precipitate an oil. The oil was separated, dried and then crystallized from Skelly'solve B hexane'hydrocarbons to give 28.0

grams ofisoamylmandelic acid melting at 125.5 to 126.6

degrees centigrade.

Calculated for C H O C, 70.22; H, 8.16. Found: C, 70.29; H,"8.21.

PREPARATION 2 B-(2,2-dimethylpyrrlidyl) ethylchloride hydrochloride ,8-(2,2,-dimethylpyrrolidyl)ethylchloride hydrochloride was prepared in. quantitative -yield from ,B-(LZ-dimethylpyrrolidyDethanol [Moffett and White, I. Odg. Chem., 17, 407 (1952)] by dissolving 85.9 grams (0.60 mole) of fi-(LZ-dimethylpyrrolidyl)ethanol in 250 milliliters of dry Q benzene, saturating the resulting solution with dry hydrogen chloride, and then slowlyadding 118.9 grams (1.0

. Cl, 35.84; N. 6.98.

EXAMPLE 1 fl-pyrrolidylethylisoamylmandelate and its hydrochloride A mixture of 9.5 grams (0.043 mole) of isoamylmandelic acid (a-isoamyl-u-phenyl-a-hydroxyacetic acid), 7.3 grams (0.43 mole) of fl-pyrrolidylethyl chloride hydro- Similarly, other acid addition salts or fl-pyrrolidylethyl isoamylmandelate may be prepared by reaction ofthe latter compound with 21 preferably anhydrous acid. The quaternary salts maybe prepared by reaction of B-pyrrolidylethyl isoamylmandelate with usually a large molar equivalent excess of the selected alkyl halide, preferably lower-alkyl chloride, bromide, or iodide.

EXAMPLE 2 5-(2-methylpyrrolidyl)ethyl isoamylmandelate hydrochloride EXAMPLE 3 [i-(2-methylpyrrolidyl)ether isoamylmandelate bromide metho- A benzene solution of 0.0185 mole of B-(Z-methylpyrrolidyl)ethyl isoamylmandelate was prepared by shaking an aqueous solution of 6.8 grams of the hydrochloride with fifteen milliliters of a forty percent aqueous solution of sodium hydroxide and then extracting the whole with ether. The benzene layer was separated, washed thoroughly with water and then dried by vacuum distillation of 'a portion of the benzene. The dry benzene solution was filtered and then mixed in the cold with 45 grams (0.475 'mole) of methyl bromide. The resulting solution was maintained in a tightly stoppered flask at room temperature for about four days. After the first few hours, crystals began to appear in the flask. The reuslting precipitate was filtered and dried to yield 5.5 grams, a yield of seventy percent of the theoretical, of B-(Z-methylpyrrolidyl)ethyl isoamyhnandelate methobromide melting at 148 to 151 degrees centigrade.

Calculated for C H BrNO C, 58.87; H, 8.00; N, 3.27; Br, 18.65. Found: C, 58.77; H, 8.14; N, 3.14; Br, 18.35.

Similarly, other quaternary ammonium salts of fl-2- methylpyrrolidyl)ethyl isoamylmandelate may be prepared by reaction of the latter compound with the selected alkyl halide, preferably lower-alkyl chloride, bromide, or iodide, e.g., ethyl bromide, ethyl chloride, methyl chloride, or methy iodide.

EXAMPLE 4 3-(2,2-dimethylpyrrolidjl.)ethyl isoamylmandelate hydrochloride, 18.2 grams (0.18 mole) of anhydrous potassium 1 carbonateand about fifty milliliters of met-hylethylketone was stirred at the refluxing temperature of the methylethylketone for nineteen hours. The reaction mixture was then cooled, filtered and the filter cake washed with ether. The filtrate and washes were combined and extracted with dilute aqueous hydrochloric acid. The acid solution was made basic with diluate aqueous sodium hydroxide and the thus-produced oily precipitate of ,B-pyrrolidylethylisoamylmandelate extracted withether. The ether solution was dried with anhydrous potassium carbonate the potas-- sium carbonate removed and the ether solution made acidic with dry hydrogen chloride. The 12.1 grams, a yield of eighty percent of the theoretical, of white precipitate of fi-pyrrolidylethyl isoamylmandelate hydrochloride was'recrystallized from a mixture of methylethylketone' to 161.5 degrees centigrade.-

Calculated for cigl-l O NClz C1, 9.5 7. Found: 9.54.

V chloride Following the procedure described in Example 1, eight grains (0.03 mole) of isoamylmandelic" acid, 7,2 grams (0.036 mole) of fi-(2,2-dimethylpyrrolidyl)ethyl chloride hydrochloride and a large'exces's of potassium carbonate were reacted together inmethyl-isobtitylketone at degrees'centigrade for eight hours. There was thus obtained an 81.1 percent yield of ,8-(2,2-dimethylpyrrolidyl)ethyl isoamylmandelate hydrochloride. The hydrochloride, after conversion to the free base and then back to its hydrochloride and a recrystallization from a mixture of ethyl acetate andSkellysolve B (hexane hydrocarbons), melted at:113.5 to 116 degrees centigrade.

Calculated for C H 3ClNO N, 3.69; Cl, 9.23.

7 EXAMPL 5 )3-(2,2-dimethylpyrr0lidyl)ethyl cyclopentylmandeldte hydrochloride Following the procedure described lin, Example 1,.a' mixture of. 11.0 grams (0. 05 mole) 0f. cyclopentylman- N, 3.83; Cl, 9.17.

EXAMPLE 6 ;8- (2,2-dimethylpyrrolidyl) ethyl cyclopentylmandelate methobromide fi (2,2-dimethylpyrrolidyl)ethyl cyclopentylmandelate methobromide was preparated in 64 percent yield by the reaction of an ether solution of B-(2,2-dimethylpyrrolidy1)- ethyl cyclopentylmandelate (prepared in the manner described in Example 3) with a large molar equivalent excess of methyl bromide for 48 hours in a sealed glass tube. The pure product melts at 192 to 194 degrees centigrade.

Calculated for C H BrNO Br, 18.13. 18.16.

Following the procedure described in Example 1, other acid addition salts of B-(2,2-dimethylpyrrolidyl)ethyl isoamylmandelate, S-(Z-methylpyrrolidyl)ethyl isoamylmandelate, 8-(2,2-dimethylpyrrolidyl)ethyl cyclopentylmandelate, B-(Z-methylpyrrolidyl)ethyl cyclopentylmandelate, fl (2,2-dimethylpyrrolidyl)ethyl a-cyclopentyl-whydroxybutyrate, and other alkyl pyrrolidylalkyl esters of hydrocarbon substituted mandelic acids and other a-hYdIOXY acids may be prepared by reaction of the selected free base with a chemical or molar equivalent of the selected acid.

Following the procedure described in Example 3, the acid addition salts of the compounds described hereinbefore may be converted to quarternary ammonium salts, preferably lower-alkyl bromides, chlorides, or iodides, by reaction of the selected free base with the selected alkyl halide.

It is to be understood that this invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and Found: Br,

equivalents will be apparent to one skilled in the artand the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of (1) pyrrolidyl alkyl esters of the structural formula:

H O O 1 ll wherein R is a five carbon cyclic hydrocarbon group and Am is an N-pyrrolidyl radical selected from the group consisting of pyrrolidyl and methyl substituted pyrrolidyl; (2) acid addition salts thereof; and (3) quaternary ammonium salts thereof.

2. A compound according to claim 1 wherein R is cyclopentyl.

3. A compound according to claim 1 wherein Am is 2,2-dimethylpyrrolidyl.

4. A compound according to claim 2 wherein Am is 2,2-dimethylpyrrolidyl.

5. 18 (2,2-dimethylpyrrolidyl)ethyl-a-hydroxy-a-cyclopentyl-a-phenylacetate hydrochloride.

6. B (2,2-dimethylpyrrolidyl)ethyl-u-hydroxy-ot-cyclopentyl-ot-phenylacetate methobromide.

References Cited in the file of this patent UNITED STATES PATENTS 2,541,634 Blicke Feb. 13, 1951 2,648,666 Robinson Aug. 11, 1953 2,655,511 Woodrulf Oct. 13, 1953 2,659,725 Cusic et al. Nov. 17, 1953 2,735,847 Blicke Feb. 21, 1956 2,752,385 Cusic et a1. June 26, 1956 FOREIGN PATENTS 291,676 Switzerland Oct. 1, 1953 OTHER REFERENCES Jr. Am. Chem. Soc., vol. 64, pp. 428-433 (1942). Helv. Chim. Acta., vol. 30, pp. 292-297 (1947). Jr. Pharm. and Exp. Therap., vol. 108, 292316 (1953). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) PYRROLIDYL ALKYL ESTERS OF THE STRUCTURAL FORMULA: 